Functional sequence variants within the SIRT1 gene promoter in indirect inguinal hernia

Inguinal hernia is a common surgical disease, for which genetic factors have been suggested to play a role. Sirtuin 1 (SIRT1), a highly conserved NAD-dependent class III deacetylase, has been implicated in human diseases. Since SIRT1 regulates differentiation and proliferation of human skeletal muscles and fibroblasts, we speculated that misregulation of SIRT1 gene, caused by DNA sequence variants (DSVs) within its regulatory regions, may contribute to inguinal hernia development. In this study, SIRT1 gene promoter was genetically and functionally analyzed in patients with indirect inguinal hernia (IIH) (n=139) and ethnic-matched healthy controls (n=148). Two heterozygous DSVs, g.69644213G>A and g.69644268T>A, and one single nucleotide polymorphism (SNP), g.69643707A>C (rs35706870), were found in IIH patients, but not in controls. Two closely-linked SNPs, g.69644217A>C (rs932658) and g.69644341G>C (rs2394443), were found in IIH patients with significantly higher frequency, compared to controls (P=0.006). The C alleles of the SNPs g.69644217A>C (rs932658) and g.69644341G>C (rs2394443) were associated with IIH (P=0.028, OR 1.600, 95%CI 1.049-2.439). These DSVs significantly altered the transcriptional activities of the SIRT1 gene promoter in cultured cells. Therefore, our data suggested that these DSVs may alter the transcriptional activities of SIRT1 gene promoter and change SIRT1 levels, contributing to IIH development as risk factors.